Osteoarthritis is characterized by primary or secondary alterations in mechanical forces and biochemical alterations in involved joints. An understanding of osteoarthritis, which develops when repair mechanisms fail to keep up with degenerative changes, requires enhanced knowledge of the reparative response. The central theme of this program project is derived from the hypothesis that primary or secondary mechanical dysfunction affects metabolic aspects of the joint with resultant aberrant chondrocyte metabolism and repair mechanisms. Extensive studies of a rabbit model of osteoarthritis in which degenerative changes follow partial resection of the medial meniscus provide the core from which natural interactions have occurred that now are culminated by this program project. Studies of repair in this model will compare reparative responses in osteoarthritis (unstable) versus stable knee joints. This study will also assess whether cartilage repair can be promoted by use of transplants of cultured chondrocytes. Further studies will define the effectiveness of mesenchymal stem cells derived from periosteum and driven to chondrogenic phenotypes in the repair of articular cartilage defects. The role of bone responses in unstable osteoarthritis models will be studied in order to focus on the interplay between subchondral bone and cartilage mechanics. The interaction of biomechanical, biochemical, physiochemical, and collagen cross-linking responses will be evaluated and compared in a model of intervertebral disc degeneration. The cellular and molecular responses to mechanical dysfunction will be studied by evaluation of signal transduction pathways governing chondrocyte gene expression, and by molecular biological studies of alterations of the extracellular matrix which affect chondrocyte metabolism. A biochemistry core will support these projects and provide technical capabilities in proteoglycan carbohydrate biochemistry to include protein sequencing, protein purification, and high pressure liquid chromatography techniques. Project personnel represent an already strong collaboration of the Department of Orthopaedics, Division of Rheumatic Diseases, Department of Biology, and the Department of Mechanical and Aerospace Engineering. These personnel have a long history of interaction in many levels as part of a Multipurpose Arthritis and Musculoskeletal Diseases Center, a unique multispecialty orthopaedic/rheumatology training grant, and the Skeletal Research Unit at Case Western Reserve University. An operational executive committee, administrative policy committee, and an external advisory committee to fully interdigitate research activities are already in place and will function to provide appropriate support for this program project.